Throughout this application, various publications are referenced by author and date. Full citations for these publications may be found listed alphabetically at the end of the specification immediately preceding Sequence Listing and the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
Erythropoietin (Epo) is a hematopoietic growth factor which stimulates the differentiation and supports the survival of cells of erythroid lineage. During fetal development the liver serves as the primary source of Epo. Shortly before birth, production of Epo in the liver decreases and the kidney becomes the primary source. In both tissues, Epo transcription is subject to physiological regulation at the level of gene transcription in response to hypoxia, a process which can be mimicked by cobalt chloride (CoCl.sub.2) in vitro and in vivo. Mechanistic studies have identified a cobalt-hypoxia, response heme protein which is capable of directly stimulating the transcription of Epo in vitro.
Injectable recombinant erythropoietin (Epo) is used currently as the therapy of choice for the treatment of anemia due to chronic renal failure. For example, Epo has been approved for the treatment of anemia associated with chemotherapy, as well as being developed for the anemia that develops as a consequence of AIDS, anemia due to prematurity and for autologous blood donation. Epo has even been suggested as a general use agent in pre-operative elective surgery. However, its extensive use could be limited by high production costs and lack of oral bioavailability. Therefore, small molecules that induce endogenous Epo will have significant utility for effective treatment of the above disorders.